Indole-3-methanesulfonamides

ABSTRACT

DERIVATIVES OF INDOLE-3-ACETAMIDE AND INDOLE-3-METHYLSULFONYL COMPOUNDS ARE PREPARED WHICH HAVE UTILITY AS SKELETAL MUSCLE STIMULANTS.

United States Patent C) 3,833,608 INDOLE-3-METHANESULFONAMIDES Clarence Stanley Rooney, Beaconsfield, Quebec, and Clarence Henry Gleason, Montreal, Quebec, Canada, assignors to Merck, Sharp & Dohme (I.A.), Rahway,

No Drawing. Original application Nov. 23, 1970, Ser. No. 92,210, now Patent No. 3,673,186. Divided and this application Sept. 15, 1972, Ser. No. 289,511

Int. Cl. C07d 27/56 US. Cl. 260-32612 R 5 Claims ABSTRACT OF THE DISCLOSURE Derivatives of indole-3-acetamide and indole-3-methylsulfonyl compounds are prepared which have utility as skeletal muscle stimulants.

This is a division of application Ser. No. 92,210, filed Nov. 23, 1970, US. Pat. 3,673,186. This invention is concerned with novel derivatives of indole that have utility as muscle stimulants. In particular the novel compounds have the following structural formula wherein R represents (1) --CONHSO X, wherein X represents (a) lower alkyl of from 1 to about 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl, either straight or branch chained, and either unsubstituted or substituted with halo such as chloro, bromo, or fluoro, or phenyl, (b) phenyl, either unsubstituted or substituted with (i) lower alkyl of 1 to about 3 carbons, (ii) di(lower alkyl) amino, wherein the lower alkyl groups have from 1 to about 3 carbon atoms, (iii) halo, such as chloro, bromo or fluoro, (iv) nitro, (v) lower alkoxy of from 1 to about 3 carbon atoms, and (vi) trifluoromethyl,

wherein R represents (i) lower alkyl of 1 to about 3 carbon atoms either unsubstituted or substituted with halogen such as chloro or fluoro,

Patented Sept. 3, 1974 (ii) phenyl-lower alkyl, wherein the lower alkyl is of 1 to about 3 carbon atoms, (iii) phenyl,

(iv) R wherein R represents lower alkyl 01. 1 to about 3 carbon atoms;

wherein R represents (a) lower alkyl of 1 to about 5 carbon atoms either straight or branch chained and either unsubstituted or substituted with such as (i) lower alkoxy of 1 to about 3 carbon atoms,

(ii) phenyl, either unsubstituted or substituted with halo, lower alkyl, or lower alkoxy,

(b) phenyl, either unsubstituted or substituted with such as (i) lower alkyl of 1 to about 3 carbon atoms,

(ii) lower alkoxy of 1 to about 3 carbon atoms,

(iii) halo such as chloro, or bromo.

R represents 1) hydrogen, (2) lower alkyl of 1 to about 3 carbons,

(3) lower alkenyl of from 3 to about 5 carbon atoms,

such as allyl, butenyl and the like;

R represents lower alkyl of l to about 8 carbon atoms,

either straight or branch chained and either unsubstituted or substituted with (a) lower alkoxy of 1 to about 3 carbons (b) lower alkylthio of 1 to about 3 carbons,

(c) halo, such as chloro, bromo, fluoro, dichloro, trichloro, or trifluoro,

R is attached to either the 5- or 6-position of the indole nucleus and represents 1) hydrogen,

(2) lower alkyl of l to about 3 carbon atoms (3) halo-lower alkyl, such as trifiuorolower alkyl wherein the lower alkyl group has from 1 to about 3 carbon atoms,

(4) halo such as chloro, bromo or fluoro,

(5) lower alkoxy-lower alkyl wherein the lower alkoxy and lower alkyl groups each has from 1 to about 3 carbon atoms.

The active agents of this invention have been found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed. The overt appearance is readily distinguishable from convulsions caused by central stimulation. The stimulation of striated muscle is useful in the treatment of disease entities characterized by progressive fatigability of the muscles such as myasthenia gravis.

Treatment with the active agents of this invention can be orally in the form of powders, granules, wafers, tablets, capsules or pills, or by injection intravenously, or intraperitoneally in suspension or in solution. The dose is from 1 to about 50 mg./kg./day either singly or on a multidose regimen depending on the severity of the disorder and the discretion of the physician.

The indole skelleton of the active compounds of this invention is prepared by standard chemical synthetic procedures well known in the art and are represented by the following reaction sequences:

METHOD A CH CH: R3 B 0001 R IIIH -N-CR R R O I II l Na NH:

III

wherein R and R are as previously defined, and R is other than chloro-, bromo-, dichloroor trichloro-lower alkyl.

When R is one of the polyhalogenated alkyls excepted from Method A above an alternate route to compound III is required in as much as the halogen group will not survive the very basic conditions provided by sodamide.

The alternate route to Compound III is represented by the following reaction sequence:

METHOD B i R; N CIEI-C-R R IV V III The diazomethyl ketone (V), and an approximately equimolar amount of an acid catalyst such as boron trifluoride etherate or the hydrobromide salt of the aniline (IV) are mixed and an excess of the aniline (IV) is added. The mixture is then heated to 175200 C. for from 10 minutes to about hours. The cooled mixture is neutralized and the excess aniline reactant is separated by steam distillation or by extraction from ether solution with dilute acid. The product is then isolated by recrystallization from a suitable solvent.

The diazomethylketones are prepared by standard techniques involving the reaction of acid chlorides with diazomethane.

The substituents in the 3-position of the indole structure are introduced by a variety of reactions depending on the nature of the substituent.

The indole acetic acids and intermediates are prepared by known methods in accordance with the following reaction scheme:

METHOD C R3 F ECHO H HzN( z)2 NL HN(CI-I;)z N

III VI last CH COOH KOH CHzCN 33 TI a F fi VIII VII The indole-3-acetic acid derivatives wherein R is monohalo-lower alkyl are prepared from Compound VII wherein R is benzoyloxy-lower alkyl according to the following reaction:

-I(CH2 C O 0 H N (CH2) NX i (R =halo-lower alkyl) VIII (2.)

Hydrogenolysis of the benzyl group of Compound VII(a) occurs readily in alcoholic solutions in the presence of a palladium catalyst to yield the corresponding 2-hydroxy-lower alkyl compound VII(b). Halogenation of VII(b) with PO1 or PBr by heating to about C. in an inert organic solvent provides the halolower alkyl compound, VII(c). Alcoholysis of the nitrile VII(c) to the ester and hydrolysis with dilute hydrochloric provides the 2-halo-lower alkylindole-B-acetic acids VIII(a).

The compounds of this invention wherein R is CONHSO X are prepared by treatment of the acid chloride of an appropriately substituted indoleacetic acid with an allgali,

metal salt of a sulfonamide of formula XSO NH as shown by the following reaction scheme:

METHOD E CH1C00H cmcocl R3 J P 015 R3 I 2 \N R2 N /-R VIII IX l XS OzNH K CH: C NHS 02X N R2 i The acid chlorides of the indoleacetic acids are prepared by treatment of the indoleacetic acid in an inert organic solvent such as glyme, (1,2-dimethoxyethane), diglyme, [bis(2-methoxyethyl)ether] or similar ether type solvents, with phosphorus pentachloride preferably at a low temperature i.e., from about to about C. and preferably under an inert atmosphere. The acid chloride is not normally isolated as such but treated directly with an alkali metal salt, such as the potassium or sodium salt, of the appropriate sulfonamide preferably in the cold. After warming to room temperature the product is isolated by treatment with water and adjustment of the pH to between about 7 and 3 with a mineral acid such a hydrochloric, sulfuric, or the like. The alkali metal salt of the sulfonamides are prepared by treatment of the sulfonamide in an alcohol with an alkali metal tertiary alkoxide such as potassium t-butoxide.

In those instances wherein X represents and one or both of R and R is (are) benzyl, the benzyl group can be readily removed by hydrogenolysis, causing R and/or R to 'be hydrogen. Such a synthesis is represented by the following equation:

METHOD F R5 CHaC ONHSOzN R H2 CHgPh HzCONHS OzNHB.

Compounds wherein R is SO NHR are prepared according to the following scheme:

METHOD G ECHO CHZSOINB R N SO 2 2 z N N/ R2 it 1 11 III XI NaHSO; P 01,

CH CH2N\ CHgSOjCl R 2 CH8 R I I U I'm VI XII CHnSOgNH-Rg XIII In the preferred method the sodium indolemethanesulfonate is obtained by heating a mixture of an indole, sodium sulfite and formaldehyde in aqueous solution at from about 50 C. to reflux for from 10 to 24 hours. The product crystallizes on cooling. This sodium salt is then treated with phosphorus pentachloride in an inert organic solvent such as an ether in the cold. After stirring for l to about 5 hours the mixture is treated with an amine of formula R NH such as ammonia, methylamine or the like. The precipitated product is separated from inorganic materials by recrystallization from benzene.

Where R is acyl, i.e.

the indolemethanesulfonamide is acetylated by standard techniques with the appropriate acid chloride or anhydride. The reaction sequence is represented by the following equation:

METHOD H CHzSOzNHg cmsomHc-w B 0001 a a R2 A xrn 1 B xrv Where R represents the indolemethanesulfonamide is treated with ethyl chlorocarbonate in refluxing acetone in the presence of an acid acceptor such as potassium carbonate for 12 to 24 hours. The resulting methanesulfonylcarbamate is then treated in the cold in an inert solvent such as glyme with an amine of formula HNR R The reaction sequence is represented by the following equation:

METHOD J on so NH 2 z z old-00,115

32 N/ l in x111 (R6==H) ii CHzSOzNHC-OCH5 R xv in i ornsozNHoN a \R R2 \i/ l XVI Compounds wherein R represents are prepared according to the following equation:

METHOD K ECHO orbs-R *5 Bills 2 R Iii 1'11 XVII m ll l l I! ems-R CH S-R R LB HNi R R R: N I l. R1

XIX XVIII The process for the preparation of these compounds comprises the reaction of an indole with a lower alkanethiol and formaldehyde in an inert solvent such as dioxane for about 10 to 24 hours to yield a lower alkylthiomethyl indole.

Oxidation of this intermediate with a suitable agent such as an alkali metal metaperiodate, lead tetraacetate, or permanganate at a temperature of 5-10 C. for from 10 to 24 hours produces the lower alkylsulfinylmethyl indole intermediate.

The above intermediate is then treated with concentrated sulfuric acid and hydrazoic acid at 40-45 C. After pouring on ice and extracting with an organic solvent, the

lower alkylsulfoximinomethylindole is obtained.

Compounds wherein R represents prepared according to the following equation:

METHOD L CH'CN 02115011 R3 R2 NaOCzH; I v11 R1 CH2- OGgH5 s I XX R l (n ooho u i cmoNH-h-R XXI R1 The appropriate indole-3-acetonitrile is treated with an alkali metal such as sodium or potassium in a lower alkanol usually ethanol at temperatures between ambient and the reflux temperature of the lower alkanol, preferably at about 50 C. for from 12 to about 48 hours, 24 hours usually being sufficient. After evaporation of the alkanol solvent, the resulting imino ester residue is slurried in ether or other inert solvent and the mixture is treated with an acid anhydride at ambient temperature or with slight warming for 12 to about 48 hours. The reaction is then quenched by pouring into ice-water and the product is isolated by standard techniques from the organic layer.

EXAMPLE 1 2-Butyl-5-methylindole Step A: Preparation of N-(2,4-dimethylphenyl)pentanamide.A solution of 22.7 g. (0.188 mole) of pentanoyl chloride in ml. tetrahydrofuran is added over 20 minutes to a stirred, ice-cooled solution of 121.2 g. (1 mole) 1-amino-2,4dimethylbenzene. After standing for several hours at room temperature the solvent is removed by distillation in vacuo. The residue is taken up in ether and extracted with 12N HCl to remove excess l-amino- 2,4-dimethylbenzene. After washing to neutrality and drying over magnesium sulfate, the ether solution is concentrated to yield 25.1 g. of N-(2,4-dimethylphenyl)pentanamide, m.p. 114-115 C.

Step B: Preparation of Z-Butyl-5-methylindole.To a stirred solution of 20.5 g. (0.1 mole) of N-(2,4-dimethylphenyl)pentanamide in 250 ml. diethylaniline under nitrogen, is added in portions, 20 g. (0.526 mole) of sodamide. The mixture is heated slowly to 220 C. and maintained at this temperature for 5 hours. The reaction mixture is cooled to about 50 C., and the excess sodamide carefully decomposed by the addition of 300 ml. of water. The organic phase is extracted into 300 ml. ether and washed with portions of cold 4N HCl and water. The ether solution is dried and concentrated to 20.2 g. of residual solid. Recrystallization from petroleum ether gives 2-butyl-5-methylindole, m.p. 73.5-75.5 C.

Employing the procedure of Example I, but substituting for the pentanoyl chloride and the 2,4-dimethylaniline used therein equivalent amounts of an acid chloride of formula R COCl and an aniline of structure NH k.

described in Table I there are produced the 1-R -2-R -R indoles also described in Table I.

2- (2,2-dichloroethyl indole Step A: Preparation of diazomethyl 2,2-dichloroethyl ketone.--A solution of 3,3-dichloropropionyl chloride (1.5 g., 0.01 mole) in ether 25 ml. is added dropwise to a rapidly stirred solution of diazomethane (0.03 mole) in 25 ml. ether at -5 C. The crude product is obtained by evaporation of the solvent and excess diazomethane and used directly in the next step. (dimethylaminomethyl)-5-methyl-2-butylindole dissolved mixture of 1.0 g. of diazomethyl 2,2-dichloroethyl ketone, 1 g. of boron trifiuoride etherate and 15 ml. of freshly distilled aniline is heated under reflux at 180 for minutes. The cooled reaction mixture is treated with an excess of sodium carbonate solution and steam distilled to remove the aniline. The solid residue is collected and recrystallized from benzene-petroleum ether.

EXAMPLE 16 2- (2,2,2-Trichloroethyl) indole Employing the procedure of Example 15, but substituting for the 3,3-dichloropropionyl chloride used therein an equivalent amount of 3,3,3-trichloropropionyl chloride, there is produced 2-(2,2,2-trichloroethyl)indole.

EXAMPLE 17 Z-ButyI-S-methylindole-3-acetic acid Step A: Preparation of 3-(Dimethylaminomethyl)-2- butyl-5-methylindole.--A solution of 6.087 g. (0.0325 mole) of 2-butyl-5-methylindole in 32.5 ml. dioxane is added dropwise to a stirred solution of 3.25 ml. of formaldehyde (25% aqueous), 7.15 ml. of dimethylamine (37% aqueous), 32.5 ml. of glacial acetic acid, and 32.5 ml. of dioxane at a temperature maintained below 0 C. After the addition is complete, the reaction mixture is allowed to warm to room temperature over a period of 18 hours. It is diluted with 300 ml. water and filtered to remove a small amount of gummy by-product. The fil- 10 trate is chilled in an ice-bath and made basic (pH 10-11) with 10N KOH. The precipitated product is filtered, washed with water and dried. Recrystallization from nhexane gives 5.0 g. (63.3%) of 3-(dimethylaminomethyl)-2-butyl-5-methylindole, m.p. 108.5110.5 C.

Step B: Preparation of 2-Butyl-3-(cyanomethyl)-5- methyl-indole.A solution of 3.42 g. (0.014 mole) of 3- (dimethylaminomethyl)-5-methyl-2-butylindole dissolved in 60 ml. dry ether is added dropwise with stirring to an ice-cooled solution of 19.5 ml. of iodomethane and stirred for 6 hours at 0 C. The precipitate is filtered, washed with ether and dried to yield 4.7 g. (87%) of the methiodide salt of 3-(dimethylaminomethyl)-5- methyl-Z-butylindole.

Without further purification, the methiodide is added to a solution of 8.93 g. potassium cyanide in 68.3 ml. of water and maintained at C. with stirring for 2 hours. After cooling, the reaction mixture is extracted with ether, the ether solution is washed with water, dried over magnesium sulfate and evaporated to a residual yellow oil, 2.9 g. (90%) of 2-butyl-3-(cyanomethyl)-5-methylindole.

Step C: Preparation of 2-Butyl-5-methylindole-3- acetic acid-The nitrile 2.9 g. (0.0128 mole), is added to a solution of 11.53 g. (0.205 mole) potassium hydroxide in 39 ml. of water and 64 ml. ethanol and refluxed for 16 hours under a blanket of nitrogen. The reaction mixture is diluted with 500 ml. water, acidified to pH 2 with concentrated hydrochloric acid and extracted with. ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated to a crystalline residue, 3.1 g. (90%). Recrystallization from petroleum ether yields 2-butyl-5-methylindole-3- acetic acid, n1.p. 106110 C.

Employing the procedure of Example 17 as depicted by Method C, but substituting for the 2-butyl-5-methylindole used therein equivalent quantities of an indole of there are produced the substituted indoleacetic acids described in Table II.

2-(2-Chloroethyl)indo1e-3-acetic acid Step A: Preparation of 2 (2-hydroxyethyl)indole-3- acetonitrile.-A solution of 2-( 2-benzyloxyethy1)indole-3- acetonitrile (1.0 g.) obtained as an intermediate in the 11 12 synthesis of the compound of Example 32 in 35 ml. of EXAMPLE 35 ethanol is hydrogenated in the presence of a catalytic amount of palladium on carbon. After separation of giggig the catalyst by filtration, the filtrate is concentrated to dryness, and the residue of 2-(2-hydroxyethyl)indole-3-aceto- 5 Step A: Preparation of Potassium Methansulfonanitrile is collected and used directly 1n the next step. Solution of 209 (022 mole) of methanesu1 Bi Preparatlon of z' l fonamide and potassium t-butoxide (24.68 g., 0.22 mole) mtr11e-2-(l-flydrqxyethynmdole 3 acetommle (200 in 450 ml. methanol is stirred for 2 hours at room temmgJ, Phosphorus tnchlbnde and of perature. The reaction mixture is then distilled to dryness uene are heated at reflux under nitrogen for 1'8 hours. The 10 and dried in high vacuum Overnight mixture is evaporated and the residue mixed with ice Step Preparation of Acid Chloride of water and sodium carbonate. Extraction with chloroform propylindole 3 acetic a Solution of 8096 provides the product, 2-(2 chloroethyl)1ndole-3-aceton1- (0035 mole) of 5 methyl z propyl indole 3 acetic acid in trile. dry glyme chilled to 0 to 5 C. under nitrogen, is added Step C3 prepafatlon of methyl Y 7.291 g. (0.035 mole) of phosphorus pentachloride. The I 3'acetate- A n Cold solutlfm of z'c'chloroethynm' mixture is stirred for 2 hours by which time solution is dole-3-acetomtr1le (220 mg.) m 5 ml. of methanol concomplete tainlng 0.05 ml. of water is saturated with hydrogen chlo- Step C: N (Methanesu1fony1) 5 methy1 2 propy1indo1e rlde sstll'rlng at room temperature for 48 hfmrs 3-acetamide.The above solution of the acid chloride is the m 13 f' fi to dryness and the resldue 0 added to the potassium salt of methanesulfonamide from treated Sodlum blcarbqnate 1 and Step A and the reaction mixture allowed to warm to room "acted Wlth methlflene fihlonde- Punficatlon by m temperature and stirred for 2 hours. Five hundred ml. of tography on alumina ylelds methyl Water is then added to the reaction mixture and the pH is dolgajacetate" adjusted to approximately 5 with dilute hydrochloric acid. Step D Preparanon of 2'(z'dfloroethyl)mdole'3'acenc The gummy solid which precipitates is extracted with 'fM acetate (100 ether, the ether extract Washed with water, dried over hydrolyzed by refiuxmg m of 20 magnesium sulfate, treated with charcoal and concentrated f q 10% hydr9ch1nc acld for 3 hours- After to a yellow oil which, on recrystallization from ethercoolmg, the benzene layer 1s evaporated to dryness to y1eld petroleum ether i ld 4 grams of product, mp. 159-- 2-(2-chloroethyl)indole-3-acetic acid. 5

EXAMPLE 34 Employing the procedure of Example 35, the amide de- 2-(2-Bromoethyl)indole-3-acetic acid rivatives listed in Table III were prepared by substituting Employing the process of Example 33 but substituting for methane Sulfonamide and Y "P PY for the phosphorus trichloride used therein an equivalent 35 3'acetlc acid of Example 35, equivalent amounts of a amount of phosphorus tribromide, there is produced 2-(2- agent of formula z z and bromoethyl)indole-3-acetic acid. 3-acetic acid respectively.

TABLE III CHzCOCl CHZCONHS 02X R 69 R N x nsozx N H H M.P. Example R R3 X 0-) 36 11 03111 H -N(CH3)2 139-144.5 37 n-C3H1 H OH! 147-148 38 11-03111 E Q 1ss211 39 11-C3H1 5-CH3 -CHF2 40 CHaO(CH2)- 5-CHa Q 41 n-CaH7 5-CH3 Q 42 ClzCHCHr- H N(cm)2 43 CHaS(CH2) H Q 44 C1(CH2)2 H Q 45 B1(CH2)2 H 46 ClaCCHr- H Q OC2H5 47 CFaCHr H 4S XI-C3H7 5-0113 49 n-CzHv 5-CH3 .2:

13* EXAMPLE so N-(Methylsulfamyl)--methyl-2-propylindole-3- acetamide A solution of N (methyl-benzylsulfamyl)-5-methyl-2- propylindole-3-acetamide (4.13 g., 0.01 mole) from Example 48 in 50 ml. of ethanol is hydrogenated over palladium on carbon in a Parr hydrogenation apparatus at an initial pressure of 50 p.s.i.g. After separation of the catalyst by filtration, the filtrate is concentrated to dryness and the residue is recrystallized from benzene to give N (methylsulfamyl 5 methyl-2-propylindole-3-acetamide.

EXAMPLE 51 S-Methyl-2-propylindole-3-methanesulfonamide Step A: Preparation of sodium 5-methyl-2-propylindole 3 methanesulfonate.5 Methyl-2-propylindole (17.3 g., 0.1 mole) and sodium sulfite (50.4 g., 0.4 mole) are suspended in water (250 ml) and heated to gentle reflux with stirring. Aqueous formaldehyde (25 ml. 36.2%, 0.3 mole) is added and the mixture is refluxed for 18 hours. The reaction mixture is cooled and the product that crystallizes is collected by filtration and recrystallized from aqueous sodium bromide solution to give sodium 5- methyl-2-propylindole-3-methanesulfonate.

Step B: Preparation of 5 methyl 2-propylindole-3- methane sulfonamide.-To a suspension of sodium 5- methy1-2-propylindole-3-methane sulfonate (14.5 g., 0.05 mole) in ethyl ether (250 ml.) at 0-5 C. is added phosphorus pentachloride (10.4 g.,'0.05 mole) and the mixture is stirred for 2 hours. Maintaining the temperature of the reactionv mixture at 0-5 C. ammonia gas (0.1 mole is bubbled slowly into it. The precipitate consisting of sodium chloride, ammonium chloride and product is extracted several times with benzene. The extracts are concentrated to incipient cloudiness and then cooled to precipitate 5 methyl 2-propylindole-3-methanesulfonamide.

Employing the procedure of Example 51 but substituting for the 5-methyl-2-propylindole used in Step A and the ammonia used in Step B, equivalent amounts of 1-R 2-R -5 (or 6)-R, -indole and an amine of formula R NH respectively identified in Table IV, there are produced the N R 1-R -2R -5 (or 6)-indole-3-methanesulfonamides also identified in Table IV.

5-Methyl-2-propylindole-3-methanesulfonacetamide 5 Methyl-2-propylindole-3-methanesulfo namide (13.3 g., 0.05 mole) from Example 51 is refluxed in acetyl chloride (35 ml.) for one hour. The excess acetyl chloride is removed by distillation in vacuo. The residue is treated with a large excess of water and the solid residue is collected and dissolved in warm sodium bicarbonate solution. Acidification of the filtered solution with acetic acid causes precipitation of S-methyl-2-propylindole-3- methanesulfonacetamide which is purified by recrystallization from aqueous ethanol.

Employing the process of Example 56 but substituting for the 5 methyl-Z-propylindole-3-methanesulfonamide and the acetyl chloride utilized therein equivalent amounts of the 1-R -2-R -5 (or 6)-R -indole-3-methanesulfonamides and acyl chlorides of formula R' COCI described in Table'V, there are produced the 1-R -2-R -5 (or 6)-R -indole-3-methanesulfonacylamides also described in Table V.

TABLE V CH2SO2NH2 a CHgS ()zNHCOR R R C()C1' fi W in in Example R R2 R3 R7 57 CH3 l'l-C3H7 5-CF3 58 CH3 n-C4 o 5-N0z Q 59 H n-C3H1 5-CH3 CH2CH2- 11-03111 5-CH3 'C3H7 n-C3H 5-CF3 OHCl3 I1-C3H1 5-CH3 OHF2 l'l-C3H7 5-CH3 "C193 EXAMPLE 64 N- 5-Methyl-2-propylindole-3-methanesulfonyl -N',N- dimethylurea Ethylchlorocarbonate (7.2 g., 0.066 mole) is added with stirring over a period of 3 hours to a mixtureof 5-methyl-2-propylindole-3-methanesulfonamide (13.3 g., 0.05 mole) and anhydrous potassium carbonate in acetone (60 ml.). The mixture is stirred and refluxed for 18 hours, cooled and filtered. The solid residue is dissolved in water (150 ml.), filtered, and acidified with concentrated hydrochloric acid to congo red which precipitates crude N-(S-methyl 2 propylindole3-methanesulfonyl)ethyl carbamate intermediate. The precipitate is collected on a filter, washed and dried. The sulfonylcarbamate (16.9 g. 0.05 mole) is suspended in glyme (200 ml.), cooled to 0-5 C., and treated with dimethylamine (6.75 g., 0.15 mole). After Warming to ambient temperature spontaneously, the solvent and excess amine are evaporated under reduced pressure and the residue; is heated at -120 C. at 5 mm. Hg for 6 hours. The residue is recrystallized from aqueous ethanol to give N-(S-methyl 2 propylindole-3-methanesulfonyl N',N'-dimethylurea.

Employing the procedure of Example 64, but substituting for the 5-methyl-2-propylindole-3-methanesulfonamide and the dimethylamine utilized therein equivalent amounts of the 5 (or 6)-R -2-R -indole-3-methanesulfdi1- amides and the amines described in Table VI, there are produced the 5 (or 6)-R -2-R -indo1e-3-methanesulfonylureas also depicted in Table VI.

15 16 TABLE VI of 3 hours, and stirring is continued at this temperature for an additional 2 hours. The reaction mixture is poured CHZSOzNHZ @CICOCQH into ice-water. The chloroform layer is separated. The Bi aqueous layer is neutralized with aqueous sodium hyl droxide solution and extracted with chloroform. The com- HN bined chloroform extracts are dried over magnesium sul- R1 fate and concentrated to dryness. The residue is recrystal- 0 R lized from low-boiling petroleum ether to give S-methyl- CH2 8 2-propyl3 methylsulfoximinomethylindole. R3 Employing the procedure of Example 68 but substl- Ra tuting for the 5-methyl-2-pr0pyl1ndole and methanethiol N utilized therein, equivalent amounts of the l-R -2-R -5(or 6)-R -indoles and thiols of formula R SH, described in Table VII there are produced the 1-R -2-R -5(or 6)-R -3- R1 R2 R3 R8 R -sulfoximinomethylindoles also described in Table VII. filfi'. H n-CaHw 5-CH3 H I H TABLE VII 66 H n-CsH 50H; CH3 H NH 67 CH5 1 -CaH1 -C s C2115 CH3 @RmsH/HCHO CH2S RW .1 EXAMPLE 68 a @[Ol l 3 v R @HN /H SO, -It 5-Methyl-2-pr0pyl-3-methylsulfoximmomethynndole I N Step A: Preparation of 5-methyl-2-propyl-3-methylthiomethylindole.A solution of 'S-methyl-Z-propylindole R1 R R R (17.3 g., 0.1 mole) in dioxane (100 ml.) is added drop- Example: wise with stirring to a solution of formaldehyde (25 ml., 69 H l'l-CsH1 G-CHa CH3 25% aqueous) and methanethiol (10 g.) in dioxane (100 218%: 218 ml.) at 0-5" C. After addition is complete the reaction n-C4Hn 5'OHs0(CH -CH3 mixture is allowed to warm to ambient temperature over a period of 18 hours. Volatile materials are distilled in EXAMPLE 73 vacuo, and the residue is taken up in chloroform. After 1 washing with water and drying over magnesium sulfate, 5'Methyl'z'propyhndole'3'N'acety acetaml e the chloroform solution is concentrated to a small volume S-Methyl 2 propylindole-3-acetonitrile (2.12 gms.) and 1116 Solid fesidllc 0f Y 'P PY y in absolute ethanol (10 mls.) is added to sodium metal methylindole is collected by filtration. (.046 gms.) in absolute ethanol (50 mls.). The reaction Step B! Preparation of Y 'P PY y is warmed to 50 C. for 24 hours. When reaction is comfinylmethylindole-5-Methyl 2 p p y plete, the ethanol is evaporated in vacuo leaving a mixmfithylindole g! mole) from p A is added ture of the imino ester and sodium ethoxide. To this o a -5 M s lu n f i m m p ri e (210 ml-, residual mixture is added absolute ether (50 mls.), then 0.105 mole) at 0 C. The mixture is stirred at ice-bath 40 acetic anhydride (3 mls.), and then the reaction is stirred temperature Overnight The P ipitated sodium iodate is at room temperature for 24 hours. The reaction mixture separated by filtration and the filtrate is extracted with is poured onto ice-water, stirred for 4 hours, and the ether chloroform. The extract is dried over magnesium sulfate layer is then separated, washed with bicarbonate, dried, and concentrated to dryness. The residue is recrystaland evaporated in vacuo. The S-methyl-Z-propylindole-3- lized from acetone-ether to give 5-methyl-2-propyl-3- N-acetylacetamide is obtained by recrystallization from methylsulfinylmethylindole. ethanol. Step C: Preparation of S-methyl 2 propyl-3-methyl- Employing substantially the procedure of Example 73 sulfoximinomethylindole.5-Methyl 2 propyl-3-methbut substituting for the S-methyl-2-propylindole-3-acetoylsulfinylmethylindole (2.5 g., 0.01 mole) from Step B, nitrile and the acetic anhydride used therein the 1-R -2- is dissolved in 10 ml. of chloroform and to the solution R -5(or 6)-R -indole-3-acetonitriles and acid anhydrides is added concentrated sulfuric acid (2.5 ml.). The mixof formula (R CO) O described in Table VIII, there are ture is warmed to 43 C., and hydrazoic acid (0.02 mole) produced the 1-R -2-R -5('or 6)-'R -indole-3-N-acetylacetin 10 ml. of chloroform is added dropwise over a period amides also described in Table VIII.

TABLE VIII 0 O CHzCN CHZ(HJNH(IBR" R3 1! e Example R1 R2 R R" 74 H oH3o(oH2) 5-CH 11-03111 75 H CHaS(CHz)2 H -(CH2)20CH H n-CaI-Iv G-CHa 77 H I'I-C3H7 5-CF3 (CH2)2 -CHa 78 H n-C4Ha 5-CFs -CH2- OCHa 79 CHa- 11-03111 5-CF3 The amount of muscle stimulant agent to be employed will depend upon the age, condition, weight, and other factors relevant to the animal to be treated and necessarily needs to be individualized by the physician or veterinarian for each patient. A suitable unit dosage form for oral administration is described in the following example.

EXAMPLE 84 Capsules containing 25 mgs. of active ingredient N-(Methanesulfonyl) 5 methyl-Z-propyl-indole- 3-acetamide 25 Corn starch U.S.P. 10

Lactose U.S.P. 130

What is claimed is: 1. A compound of the structural formula wherein R is a member selected from the group consisting of (a) hydrogen, and (b) lower alkyl;

R is a member selected from the group consisting of (a) lower alkyl, (b) lower alkoXy-lower alkyl, =(c) lower alkythio-lower alkyl, and (d) halo-lower alkyl;

R is a member selected from the group consisting of (a) hydrogen, (b) lower alkyl, (c) halo-lower alkyl,

(d) halo, and (e) lower alkoxy-lower alkyl; and R is a member selected from the group consisting of hydrogen, loweralkyl, and acyl of the formula wherein R is a member selected from the group consisting of (a) lower alkyl,

(b) halo-lower alkyl, (c) phenyl-lower alkyl, P y

wherein R and R are members selected from the group consisting of (i) hydrogen, (ii) lower alkyl, and (iii) phenyl-lower alkyl. 2. The compound of Claim 1 wherein R is hydrogen. 3. The compound of Claim 1 wherein R and R are loweralkyl, and R is hydrogen.

4. The compound of Claim 1 wherein R is loweralkyl. 5. The compound of Claim 1 wherein R R and R are loweralkyl.

References Cited UNITED STATES PATENTS 3,297,717 1/1967 Gould et al. 260326.12R

JOSEPH A. NARCAVAGE, Primary Examiner 

